Drug users account for a substantial proportion of AIDS cases; yet have received disproportionately less benefit from highly active antiretroviral therapy (HAART) than non-drug users. Recent reports have shown that HAART is under-utilized among drug users, and that persons with a history of injection drug use may be less likely to achieve the level of adherence necessary to maintain viral suppression than non-drug users. In order to improve both access to HAART and adherence among HIV-infected drug users, new models of integrated HIV-related and substance abuse treatment are rapidly evolving. One innovative model by which to deliver such treatment, provision of HIV primary care on-site in a methadone maintenance program has been shown to improve health outcomes in several studies. Directly observed therapy (DOT), effective in treating tuberculosis in methadone programs and other settings, is a logical extension of this model that has the potential to markedly enhance adherence with HAART. However, only preliminary findings from studies of the effectiveness of DOT for HIV have been reported, and these data are not consistent. While 80-100% of HIV DOT patients have achieved undetectable viral loads in some uncontrolled studies, other pilot DOT studies have found that the proportion achieving this outcome is 60-65%. In addition, DOT for HIV may paradoxically increase the risk of drug resistance by fostering moderate improvements in adherence. Rigorous data are necessary to judge the contribution of DOT to the success of HIV treatment among drug users, particularly among drug users in methadone maintenance treatment. By performing a randomized trial of HAART DOT in methadone maintenance clinics at which HIV primary care is provided, we will be able to evaluate the efficacy and cost-effectiveness of DOT. The specific aims of this proposal are: (1) To determine in a randomized trial whether directly observed HAART, provided on-site at a methadone clinic during a 24-week study period, is more effective than self-administered HAART for reducing HIV viral load and increasing CD4 count, (2) To assess the durability of DOT as an adherence-enhancing intervention by comparing long-term adherence in the DOT and self-administered groups, using self-report and electronic monitors to measure adherence 3, 6, and 12 months after DOT is discontinued, and (3) To perform cost, cost-offset, and cost-effectiveness analyses of directly observed HAART.